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WEDNESDAY, Dec. 5, 2012 (MedPage Today) — Genetic microarray testing may be a better means of prenatal screening for abnormalities than karyotyping, the current standard of care, researchers found.

In a large cohort study, microarray found clinically relevant abnormalities that weren't picked up on karyotyping in 6 percent of samples with a structural anomaly and in 1.7 percent of samples that were flagged due to advanced maternal age or positive screening results, Ronald Wapner, MD, of Columbia University Medical Center, and colleagues reported in the Dec. 6 issue of the New England Journal of Medicine.

The study was one of three published in that issue comparing microarray versus karyotyping in various diagnostic settings, including stillbirth.

"These data indicate a benefit to chromosomal microarray analysis as a standard part of prenatal testing, bearing in mind that, as with karyotyping, the detection of variants of uncertain clinical significance present a challenge for counseling and cause anxiety," Wapner and colleagues wrote.

Aleksandar Rajkovic, MD, PhD, chief of genetics at the University of Pittsburgh Medical Center, who was not involved in any of the studies, told MedPage Today that some clinicians have already made the switch to microarray for prenatal genetic testing.

"Hopefully it represents the tipping point in favor of what some of us have been doing for the past few years," Rajkovic said. "I think general practitioners are likely embrace this new technology."

Microarray a Newer Technology

Karyotyping has been used since the 1960s to diagnose genetic disease prenatally, and involves looking at live cells under the microscope to see large differences in chromosomes that may pinpoint an abnormality.

Microarray, on the other hand, offers a higher resolution view at the DNA level to see copy-number variants, or missing or extra pieces of DNA. Where karyotyping can't see chunks of DNA below 3 million base-pairs, microarray can get it down to a few thousand base-pairs.

Indeed, microarrays have been recommended as the first line diagnostic test for evaluating developmental delays and structural malformations in young children.

But only small trials have evaluated its use in pregnant women who've been flagged with a risk factor genetic disease — so it's not clear if the microarray can detect everything that is picked up by karyotyping.

So Wapner and colleagues conducted a large, prospective study of prenatal diagnostic samples from 4,406 women who underwent prenatal genetic testing for a host of reasons, including advanced maternal age, abnormal result on Down's syndrome screening, and structural anomalies on ultrasound.

Each sample was split in two and had both karyotyping and microarray analysis.

They found that microarray was able to identify all of the aneuploidies and unbalanced rearrangements seen on karyotyping — but it didn't pick up disorders seen on the larger chromosome level, including balanced translocation and fetal triploidy.

The technology was, however, able to better zoom in on gene-level disease.

There were findings of uncertain clinical relevance in 3.4 percent of samples that were normal on karyotyping, and 72.3 percent of these weren't easily dismissed as likely to be benign.

The concern with an increase in uncertain findings is the toll that it could take on patient anxiety, and the "biggest fear is that a woman terminates a pregnancy because of a finding with unclear significance," Rajkovic said.

That's where the importance of genetic counseling would come in: "It's very important that pre- and post-test counseling is performed by genetics professionals," he said.

Wapner and colleagues noted that if data available in 2012 were used to make the diagnoses in this study, only 56 of the 94 uncertain results would have been so — 30 are now clearly pathogenic and 8 are now likely to be benign.

Use in Stillbirth Examined

In a second study, Uma Reddy, MD, MPH, of the National Institute of Child Health and Human Development, and colleagues, found that microarray testing was also better at providing a genetic diagnosis in stillbirth.

Research estimates that 6 percent to 13 percent of stillbirths involve genetic abnormalities, but the true prevalence may be higher. Microarray could help discern whether that's the case — and it doesn't require live cells, an advantage in stillbirth.

So Reddy and colleagues assessed samples from 532 stillbirths, and found that microarray analysis yielded results more often than did karyotyping.

It was also better at detecting genetic abnormalities, including both aneuploidy and pathogenic copy-number variants, showing a 41.9 percent increase in detection.

Microarray also identified more genetic abnormalities in specific subgroups, including 443 antepartum stillbirths, and in 67 stillbirths with congenital abnormalities.

Again, microarray identified more abnormalities of unknown significance than karyotyping, they reported, but they concluded that it "could be useful in cases of stillbirth in which karyotyping results cannot be obtained or in cases in which there are congenital abnormalities."

The third paper in the series involved a case report of a genetic condition, called CHARGE, that could not have been detected prenatally by ultrasound, karyotyping, or microarray.

They found them at 8q12.2 in the at CHD7 gene — a pathogenic locus in CHARGE syndrome — and at 6q13 in LMBRD1, a pathogenic locus in a recessive disorder of vitamin B12 metabolism.

Kim McBride, MD, of the Center for Molecular and Human Genetics at Nationwide Children's Hospital in Columbus, Ohio, who was not involved in the study, told MedPage Today that the case report presents an interesting application of this type of sequencing technology, which currently takes about a month to 6 weeks to perform.

"In this study, they were able to get the DNA, prepare it, analyze it, and report within 2 weeks, which is a very rapid turnaround," McBride said.

"Where this will fit in clinically, I'm not quite sure," he added. "But it's a very interesting application of the technology."

With Power Comes Pitfalls

In an accompanying editorial, Lorraine Dugoff, MD, of the University of Pennsylvania, wrote that the studies "highlight the power and complexity, and some of the pitfalls, of using new genomic technology in clinical practice."

She said the "major disadvantage is the inability to interpret the clinical significance of a new, previously unreported copy number variant or to accurately predict the phenotype of the pathogenic copy number variants."

Thus, it will be critical to develop large databases of copy number variants to better determine which are benign versus pathologic, and that involving pre- and posttest genetic counseling will be "critical."

"As we get better catalogs [of copy number variants], the number of things we can't interpret will go down," McBride said, adding that such databases of determined pathologic versus benign findings are growing at a rapid pace.

Microarray also comes at a similar price tag as karyotyping, with a range of $1,500 to $2,000, compared with $1,000 to $1,500 for the older technology. Both, however, involve invasive testing that carries a slight risk of miscarriage.

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